Patients suffering from asthma or any of many other lung diseases require delivery of medication to the bronchi or to the lungs. At the present time there are three major ways of delivering aerosol treatment or medication to such patients, namely (1) nebulizers, which may be of the (a) venturi-jet type, or of the (b) ultrasonic piezoelectric type which produce aerosols from drug solutions, (2) metered dose inhalers (MDI) consisting of fluorocarbon or other gas pressurized canisters. Dry powder inhalers (DPI) may be (a) Passive or (b) Active. DPI also provide metered doses if sufficient suction is supplied by the patient.
Metered dose inhalers both MDI and DPI are superior to nebulizers because they are readily portable, and do not generally require an external power source such as compressed air or electricity. MDI and DPI are also capable of generating aerosols that are suitable for inhalation, more efficiently, reliably and cost effectively. The pressurized canister type of aerosol generator (MDI) includes a valve, which, when actuated, causes dispersement of a metered quantity of drug.
Because MDIs have previously used a chlorofluorocarbon as the propellant, and chlorofluorocarbons are believed to have a highly adverse effect on the ozone layer surrounding the earth, they are gradually being phased out to be replaced by the environmentally more friendly hydrofluorocarbons (e.g., HFC 134a and 227).
Such metered dose inhalers have become popular in that a droplet aerosol consisting of the drug particles and the fluorocarbon propellant is generated. The fluorocarbon propellant evaporates rapidly, and leaves smaller drug particles and clumps of particles, at least some of which are on the order of 1-3 microns aerodynamic mass median diameter which is the ideal size range for medication aerosols in humans. Unfortunately, many of the particles remain in larger clumps, and do not reach the necessary areas in the bronchi and lungs.
There are some currently available powder inhalation systems which do not require a propellant. However, they do not function very effectively unless the patient can generate flow rates greater than 30-60 liters per minute, since it is the energy provided by the patient's forceful inhalation that not only mobilizes the powder but also breaks up the clumps thus preparing it for inhalation, in contrast with the high pressure of the fluorocarbon or other propellant in metered dose inhalers which accomplish the same end. The patient's inhalation then carries the medication aerosol into the air passages via a mouthpiece whichever aerosol generation method is used. Such current powder inhaler systems require strong inhalation on the part of the patient. They have not worked effectively with patients who cannot inhale vigorously.
In the metered dose inhalers noted above, it is common practice to include surfactants such as oleic acid. This presents problems. The fluorocarbon-medication suspension emerges as a liquid jet from the end of the valve stem or from the end of a cannula attached to the valve stem through which the metered dose inhaler contents have been forced and about 80 percent of it is deposited within three or four centimeters of the end of the valve or cannula. This results in an inefficient delivery system. It further has the disadvantage that large amounts of the surfactant material are deposited on the lining of the trachea, and the first few bronchi. It has been demonstrated that this causes injury to the airway lining with ulceration. Using a pure powder medication should avoid such problems, since it is the excipients in the formulation, rather than the medication that may cause this problem.
Over a period of the last 25 years aerosol therapy has become a mainstay of the treatment of airway diseases, particularly asthma and chronic obstructive pulmonary diseases, such as chronic bronchitis and emphysema as well as bronchiolitis and bronchiectasis (e.g., cystic fibrosis). It is also becoming increasingly important for delivery of antibiotics directly to the airway for chronic illnesses such as cystic fibrosis, for treating a type of pneumonia in immunosuppressed patients (e.g., in AIDS), and for providing a new class of medications (sodium channel blockers) in cystic fibrosis to "lubricate" the secretions and make them easier to cough up or remove as a result of the action of cilia. Other aerosol medications include mucolytic agents to thin secretions, the newest of which is deoxyribonuclease made by a recombinant method (rhDN-ase). Within about the last year exciting developments have occurred with regard to the delivery of several important peptide hormones by the aerosol route, because they would otherwise be inactivated by stomach acid if they were ingested. Most recently, there has been very .interesting work from the National Institutes of Health (Dr. R. Crystal), showing that genes can be inserted into inactivated common cold viruses, and delivered by the aerosol route to mice with a missing gene which can, in this way, be replaced. Even more recently, the New York Times reported that the first experiments in humans were now being undertaken using the same methods to attempt to correct the genetic defect of cystic fibrosis, thus actually curing the disease. Thus the future for an ever increasing role for aerosols in pulmonary and even systemic disease therapy looks very promising.
Aerosol delivery systems generally fall into one of two categories, either (1) active or (2) passive. (1)"Active" devices include (a) metered dose inhaler (MDI) and (b) wet nebulizers. The pressurized canister metered dose inhaler (a) MDI [which] generates the aerosol and directs it towards the patient independently of the patient's force of inhalation. This provides aerosol to the patient in a manner similar to so called "wet nebulizers" that aerosolize a drug solution (jet nebulizers using the venturi principle, the energy source being compressed air which also serves to direct aerosol towards the spontaneously breathing or ventilation assisted patient, and ultrasonic nebulizers utilizing high speed vibration of a piezo-electric crystal and a blower fan to carry the medication aerosol to the patient). These are all active aerosol devices, since with the jet nebulizer it is the flow of oxygen or air through the device that creates the aerosol and drives it towards the patient who can then breathe in from a mouthpiece or mask, while with the ultrasonic nebulizer the aerosol is generated into a space from which it can be inhaled by the patient breathing normally to inhale the mist with each normal inhalation, even if that inhalation is not vigorous. Furthermore, a blower can be incorporated which pushes the aerosol from the ultrasonic generator toward a mask or mouthpiece from which the patient inhales.
In contrast, currently available powder inhalers are "passive" devices in that the drug powder must reside in a small reservoir from which the patient can suck it by creating a relatively high inspiratory flow rate, usually over 30 L/min (liters per minute), and sometimes as high as 90-120 L/min if the optimum dose of medication is to be provided. This type of device has the advantage that aerosol is inhaled automatically when the patient inhales vigorously, but has the disadvantages that (a) there is considerable variability in dose depending upon how vigorously the patient inhales, (b) during severe episodes of asthma it may not be possible to create the high flow rates necessary to get a full dose of the drug (this is particularly true of children under the age of 6), and (c) the greatest efficiency for aerosol inhalation is achieved at low inspiratory flow rates, 45 L/min and below, because at high flow rates small particles have greater inertia and therefore fore act like larger particles, thereby tending to be deposited in the back of the throat and around the larynx by impaction rather than being carried into the airways of the lungs where the medication must be deposited to be effective. Another disadvantage of some widely prescribed current powder systems relates to exposure to the humidity of the environment of the drug reservoir where the fine particles are stored. Since many drug particles are very hygroscopic, repeated or continual exposure to humidity will greatly reduce the available dose due to swelling and clumping.
In recent years there has been increasing emphasis on powder inhaler systems, because they do not require pressurizing chemicals and because they provide medication on inhalation without having to devote as much time in teaching patients to coordinate aerosol discharge with inhalation (as is the case with MDI devices). The newest of these, known as a Turbuhaler, contains pure drug powder rather than drug powder mixed with lactose that is required in some of the other devices. Lactose is used to disperse the powder in most older devices. It is not a big issue, but because the particles are rather large they often cause patients to cough, whereas pure drug powders are much less likely to do so. Current powder inhaler systems are incapable of being used in patients who are breathing quietly such as infants and young children, and are of no use in ventilator circuits or with relatively uncooperative patients, nor can they be directed down thin cannulas in intubated patients.
Active systems (MDI and nebulizers) are extremely useful in the settings noted above, and indeed can be used in treating virtually all patients if appropriate adapters to the MDI canister, or to the nebulizer are used. Because MDI based systems, using appropriate accessory attachments are much more versatile, efficient, portable and cost effective, they are rapidly replacing wet nebulizers if appropriate MDI drug formulations are available. From the foregoing, it should be evident that active aerosol systems are inherently superior to passive systems, and that an active powder inhaler system would probably become the aerosol generation system of choice, and probably would supersede both current pressurized metered dose inhalers and passive powder systems currently available. If such a powder system could be made to approach the versatility of currently available fluorocarbon driven metered dose inhalers, it would likely make obsolete most other aerosol delivery systems, including nebulizer systems. It is probable that active powder systems could employ pure drug powder, and if provided with appropriate attachments, such as a valved mouthpiece or fine cannula extensions or with a mask to allow their use in infants, children and adults breathing normally, or even in asthmatic animals such as horses or cattle, as are presently available for use with metered dose inhalers, these would serve a wide variety of clinical needs in a variety of patients of all ages.
There are significant limitations of current MDIs in that metered dose inhalers are relatively inefficient because they produce mainly non-respirable particles. Another important issue with pressurized canister inhalers relates to the output of particles that range in size from about 35 .mu.um (micro meter) to about 1 .mu.m. Of this so called heterodisperse aerosol only about 30 percent (chiefly particles under 5 .mu.m) is actually capable of being inhaled. In practice this figure is closer to 20 percent. Most of the rest of the aerosol which is deposited in the throat has the potential for causing side effects, while not contributing to the therapeutic benefit.
We set forth the following characteristics as being those of an ideal aerosol system, which ideal aerosol delivery system would:
1. Be an active system with a reproducible dose output; PA1 2. Completely dispense with pressurizing chemicals and excipients (additives in the formulation that enable the system to produce aerosol, but do not contribute to therapy); PA1 3. Contain only pure drug; PA1 4. Create smaller and more uniform particles almost exclusively (smaller than 5 .mu.m), thus improving the efficiency of drug delivery to the airways of the lungs; PA1 5. Dispense doses accurately over a wide range, such as 10-1000 ug; PA1 6. Be as foolproof as possible for the patient to use; PA1 7. Be small and easily portable; PA1 8. Contain multiple doses sufficient for at least about a month of therapy; and PA1 9. Be used with a variety of adapters making the system useful in neonatology, pediatrics and adult medicine or even for veterinary medicine for treating chronic illness, acute flareups, and, if necessary, patients who are intubated, and require assisted ventilation because of inability to breathe sufficiently to provide oxygen to their bodies and remove carbon dioxide.
The result of providing almost exclusively very fine and thus "respirable" particles would be that much smaller doses would be required because the system could be much more efficient, with greatly decreased losses of medication in the throat and hopefully reduced cost. We call this approach to aerosol therapy "airway drug targeting", because the inhaled medication largely bypasses the upper airways above the larynx to be deposited fairly uniformly in the airways of the lungs below the larynx.
It is well recognized that powders in storage tend to clump together so that large amounts of energy are needed to create an aerosol cloud of an appropriate size for inhalation.